chr12-53504394-C-G

Variant names:

• chr12-53504394-C-G
• rs74090784
• NM_134323.2:c.423-3C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_134323.2(TARBP2):​c.423-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,553,002 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (70 hom.)
• Consequence: TARBP2 NM_134323.2 splice_region, intron
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.431

Genes affected

TARBP2 (HGNC:11569): (TARBP2 subunit of RISC loading complex) HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene binds between the bulge and the loop of the HIV-1 TAR RNA regulatory element and activates HIV-1 gene expression in synergy with the viral Tat protein. Alternative splicing results in multiple transcript variants encoding different isoforms. This gene also has a pseudogene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-53504394-C-G is Benign according to our data. Variant chr12-53504394-C-G is described in ClinVar as [Benign]. Clinvar id is 781258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TARBP2	NM_134323.2	c.423-3C>G		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000266987.7	NP_599150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TARBP2	ENST00000266987.7	c.423-3C>G		splice_region_variant, intron_variant	Intron 4 of 8	1	NM_134323.2	ENSP00000266987.2

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2938 AN: 152140 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00599 AC: 1150 AN: 192130 AF XY: 0.00432

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000219

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00184 AC: 2583 AN: 1400744 Hom.: 70 Cov.: 31 AF XY: 0.00164 AC XY: 1139 AN XY: 693624

Gnomad4 AFR exome AF: 0.0668 AC: 2063 AN: 30892

Gnomad4 AMR exome AF: 0.00482 AC: 155 AN: 32170

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 21306

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39346

Gnomad4 SAS exome AF: 0.000188 AC: 14 AN: 74614

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51252

Gnomad4 NFE exome AF: 0.0000928 AC: 101 AN: 1088700

Gnomad4 Remaining exome AF: 0.00395 AC: 228 AN: 57694

GnomAD4 genome AF: 0.0193 AC: 2941 AN: 152258 Hom.: 96 Cov.: 32 AF XY: 0.0184 AC XY: 1367 AN XY: 74458

Gnomad4 AFR AF: 0.0673 AC: 0.0672558 AN: 0.0672558

Gnomad4 AMR AF: 0.00661 AC: 0.00660649 AN: 0.00660649

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207125 AN: 0.000207125

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000162 AC: 0.000161679 AN: 0.000161679

Gnomad4 OTH AF: 0.0161 AC: 0.0160833 AN: 0.0160833

Alfa AF: 0.0101 Hom.: 6

Bravo AF: 0.0222

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.72		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74090784; hg19: chr12-53898178; COSMIC: COSV57199244;